A Preparedness Sample Repository to Facilitate Rapid Diagnostic Test Development and Deployment
A White Paper
Infectious disease outbreaks, even small or remote ones, may be a global threat and require a swift public health response. Accurate, accessible, and robust diagnostic tests are critical for patient management and public health response. However, when a new threat emerges, diagnostic tests may not exist and have to be developed rapidly, and then implemented by public health and clinical laboratories to support response efforts.
In the event that there are no suitable Food and Drug Administration (FDA) approved or cleared diagnostic tests, FDA has the authority to facilitate rapid deployment and use of tests under the expedited process of Emergency Use Authorization (EUA). (1) If an emergency is declared by the United States (US) Secretary of Health and Human Services, the FDA Commissioner may allow use of unapproved medical products or unapproved uses of approved medical products to aid in diagnosis of life-threatening diseases or conditions caused by infectious agents when there are no adequate, approved, and available alternatives. When reviewing an EUA, FDA relies on the totality of scientific evidence to determine that the product may be effective for the intended use in an emergency. For diagnostic tests, the scientific evidence includes validation of (limit of detection), inclusivity, exclusivity (near neighbors, pathogens with similar disease symptomology, endemic pathogens, etc.), and in silico analyses (if applicable). EUA tests may also require evidence of clinical performance using true positive and true negative samples alongside comparator methods (FDA cleared or other EUAs if available). These data, if not available before the emergency, must be generated by diagnostic test developers and included in the submission of a request for authorization.
Prior to implementing a legally distributed EUA test, clinical laboratories in the United States must satisfy regulatory requirements set forth by the Clinical Laboratory Improvement Amendment of 1988 (CLIA). (2) For the use of an unmodified, FDA cleared or approved test system (e.g., EUA test), laboratories must demonstrate that performance specifications (e.g., accuracy, precision, reportable range, reference range) obtained in their own laboratory are comparable to those established by the manufacturer. How these verification studies are performed is at the discretion of the laboratory director and often include testing a variety of samples, including positive samples with an appropriate range of analyte concentrations, samples with interfering substances or related organisms, and negative samples. For use of EUA tests, the laboratories must only test the sample types (e.g., plasma or serum) that are approved or authorized by FDA when performing diagnostic testing, therefore, it’s important to include those samples in their verification studies. Furthermore, the laboratory must also include negative and positive controls when performing testing on patient samples and comply with any additional local and state regulations that are applicable.
Access to samples and materials, which are accompanied by metadata including previous testing result and available through a nationally distributed repository, will improve diagnostic test development and the capacity of clinical and public health laboratories to respond to public health emergencies.
In the early stages of an outbreak, some types of materials may not be available or are only available to a very limited group of developers. Diagnostic test development and validation require a rich and diverse inventory of both relevant clinical sample types (e.g., eye fluids, semen, cerebrospinal fluid) and pathogens collected from the affected patient populations, which are often in very short supply at the beginning of an outbreak. The lack of relevant material and clinical specimens for test development and validation may delay response time and compromise the ability of developers to validate tests with the goal of improving patient management and strengthening the public health response to emerging infectious diseases.
Access to test materials is delayed without dedicated and centralized logistical support. There are a number of challenges associated with collecting patient samples, starting with the need for Institutional Review Board (IRB) approval and possible requirements for informed consent. Other challenges include fulfilling export and import permits requirements, intellectual property considerations, reluctance from third parties to share samples, limitations on commercial use of the specimens, difficulties transferring materials (e.g. biosafety and biosecurity concerns), the process for generating material transfer agreements (MTAs), and identifying and coordinating available personnel and facilities to collect and manage samples in an emergency. All of these challenges become more acute when the outbreak begins outside the United States because access to clinical specimens may be restricted by international policies.
When available, test materials sourced from many different providers may have varying quality and sample characterization. The use of different samples without a “gold standard” method to assess their validity (confirm the presence of a pathogen, antibodies, or other biomarkers) may lead to a lack of comparability between samples obtained from different sources. Test materials of unknown quality and associated characterization may delay EUA and the application of these tests in an emergency response.
Mock clinical samples, created by spiking a clinical matrix with the agent of interest, can sometimes be used as a substitute for natural clinical samples obtained from affected individuals. Where the emerging disease threats are known and the pathogens available, these could potentially be prepared in advance of an outbreak. However, in events where a new disease emerges, the inability to create, generate, and use contrived samples may cause delays in test performance development and validation.
CDC and other diagnostic test developers, including those in the private sector, currently lack access to sufficient numbers of samples, materials, and isolates of pathogens or related organisms (see Table 1) needed to rapidly mount emergency response efforts for emerging and reemerging disease threats. Currently, there is no centralized resource that can provide appropriate, well-characterized samples and materials that are essential for the development and validation of diagnostic tests during public health emergencies. A recent Government Accountability Office report recognized challenges faced by commercial developers of diagnostic tests for Zika. This report also identified the challenges associated with accessing well-characterized clinical samples and reference materials, as well as developing partnerships with international entities and obtaining appropriate permits to acquire samples. (3) Well-characterized samples would include metadata such as age, sex, days post onset of symptoms, pregnancy status, tests that were performed on the specimen, and the results of those tests.
|Samples with high- and low-levels of pathogen or agent||Assess analytical sensitivity/ limit of detection, test reproducibility|
|Samples from pre-symptomatic individuals||Assess test ability to diagnose before symptoms arise/ low levels of pathogen or agent/limit of detection|
|Samples from patients who present with similar symptoms but are not infected with the pathogen of interest (from US and endemic population if external to US)||Assess analyte specificity/ cross reactivity|
|Samples from patients with acute and convalescent infections||Assess ability of test to diagnose patients during and after infection/analytic sensitivity|
|Samples from patients of different ethnicities, ages, and genders||Assess ability of test to diagnose patients who may be infected|
|Samples from uninfected individuals from the same endemic region as the infected patients||Assess analytic specificity/ cross reactivity|
|Quantified stocks of well-characterized analytes, organisms, and relevant antibodies||Materials that can be used to develop contrived samples|
|Common and specific interfering substances or cross reactivity pathogens||Materials that can be used to develop contrived samples|
|Material from uninfected or unexposed individuals (pooled or from individuals) to use as a matrix for spiking, negative controls or contrived specimens||Materials that can be used to develop contrived samples|
|Stocks of common sample types, such as serum, urine, and plasma||Materials that can be used to develop contrived clinical samples|
A. Pre-Established Collection Processes, Protocols, Permits, and Agreements
Pre-established sample collection processes, protocols, shipping permits, and collaborative agreements will make it more likely that difficult-to-obtain test materials will be available when necessary. Several processes could be developed and implemented to expedite the collection of appropriate patient samples. These include the development of a sample collection protocol (including appropriate informed consent documents) that is approved by the Institutional Review Board (IRB), and obtaining provisional IRB approval for generic sample collection that can be minimally modified based on the circumstances of an outbreak. Entities that are able to collect samples in different geographic locations, both domestic and internationally, could be identified through Blanket Purchase Agreements (BPA). Processes for collection of samples, including pre-established sharing and material transfer agreements (MTA), standardized patient and clinical data collection formats, and strategic positioning of prepaid shipping materials and labels could be instituted to facilitate the sample collection processes. Negotiating pre-established contracts with national shippers and securing proper import permits (CDC, USDA, and Department of Commerce) could also help to improve the ability to rapidly and efficiently ship samples. CDC’s longstanding relationships with many external public health organizations, such as the Association of Public Health Laboratories and the World Health Organization, other US governmental agencies (including the National Institutes of Health and Department of Defense), and state public health laboratories could be leveraged to facilitate collection, characterization, and sharing of needed materials. Partnerships with governmental, commercial, and academic biorepositories are also explored to expand access to samples and materials during a response.
B. Procurement and Proper Storage of Currently Available Materials
Identifying priority emerging disease threats, and procuring and storing available materials would increase the speed that these could be distributed in an emergency. Blood, sera, plasma, and other materials collected from unaffected donors could be purchased from tissue supply companies, and then characterized and stored for use as matrices for test development and validation of contrived clinical samples. Similarly, characterized stocks of viruses, bacteria, and common interfering substances could be created by CDC and stored for production of samples to be used for both the analytical and clinical evaluation of diagnostic tests. Stability studies could be performed regularly to confirm sample integrity and the suitability of storage conditions and used to establish expiration dates of the test materials. Data collection could be standardized to establish a uniform presentation of information and data for all samples. A virtual catalog of available samples (both at CDC and other participating laboratories or repositories) could be created to facilitate searching, identification, and requests for preparedness repository samples. A web portal could be created to inform stakeholders, and to improve communication between laboratories and test developers both inside and outside of CDC.
C. Advanced Preparation of Standardized Panels
Advance preparation of panels of clinical samples, contrived samples, and pathogens (where possible), as well as production plans and agreements to produce standardized panels on demand, would provide a way to allow comparison of newly developed diagnostic tests and identify the best test to address the needs of the public health response. These panels could also be subsequently used for diagnostic test verification or proficiency testing by spiking them with the agent of interest. Protocols for the manufacture of contrived specimens that are acceptable to FDA could be pre-positioned. Methods for pathogen inactivation could be validated so that materials could be shipped easily and provided to laboratories that do not have biosafety containment capabilities.
The creation of a preparedness repository that could serve as a centralized distributor of well-characterized clinical samples, organisms, and other materials would be a tremendous resource to clinical diagnostic test developers who work in public health (federal, state, local, and territories) and the commercial sector. The CDC Biorepository (CBR), which is managed by the Division of Laboratory Systems (DLS), has over 20 years of experience with storage and management of collections and could – with appropriate financial resources – provide the required expertise and infrastructure to support a repository of specimens and materials for emergency preparedness and response activities. The materials maintained and managed within this repository could include characterized individual clinical samples (both positive and negative), pooled patient samples, bulk material (e.g., blood, serum, urine, plasma) from unaffected donors, characterized stocks of pathogens, and interfering substances or cross-reactivity organisms. The CBR could establish mechanisms and partnerships for rapid acquisition and characterization of specimens and materials, and distribution of these products for test development, validation, optimization, and verification. Furthermore, DLS has an established partnership with CDC’s Division of Scientific Resources (DSR), which has extensive experience and expertise with collecting and processing patient samples and other materials, storing select agents, creating validation and proficiency test panels, and manufacturing and shipping reagents and controls. DSR also has a United States import permit and contracts in place to obtain blood products from sources outside the US.
A preparedness repository would facilitate access to specimens and materials that may be difficult to obtain during a response. These specimens and materials would be used to improve rapid development, performance characterization, and implementation of EUA tests during a response. The CDC Biorepository has the expertise, infrastructure, and relationships to support the creation and maintenance of a centralized, national preparedness repository.
Jasmine Chaitram1, Lisa Kalman1, Brad Bowzard1, Carolyn Black2, Dennis Bagarozzi2, Reynolds Salerno1
Centers for Disease Control and Prevention, 1Division of Laboratory Systems, 2Division of Scientific Resources
The Division of Laboratory Systems thanks the following individuals for their contributions to this manuscript:
Laura Rose, CDC Office of Laboratory Science and Safety; Kim Sapsford, Food and Drug Administration; Amy Zale, Centers for Medicare and Medicaid Services; Rosemary Humes, Biomedical Advanced Research and Development Authority; Marcia Revelez, CDC Division of Laboratory Systems; and Joanne Andreadis and John Kools, CDC Center for Preparedness and Response.
- Food and Drug Administration. Emergency Use Authorizations of Medical Products and Related Authorities, Guidance for Industry and Other Stakeholders. https://www.fda.gov/RegulatoryInformation/Guidances/ucm125127external icon
- Code of Federal Regulations: The Clinical Laboratory Improvement Amendments (CLIA), 42 CFR Part 493. https://wwwn.cdc.gov/clia/Regulatory/default.aspx
- United States Government Accountability Office. Report to Congressional Requestors. Emerging Infectious Diseases, Actions Needed to Address the Challenges of Responding to Zika Virus Disease Outbreaks. GAO-17-445, May 2017. https://www.gao.gov/assets/690/684835.pdfpdf iconexternal icon